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Effect of a Single Oral Dose of Moxidectin on the Cardiac QT Interval of Healthy Volunteers

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ClinicalTrials.gov Identifier: NCT03012828
Recruitment Status : Completed
First Posted : January 6, 2017
Results First Posted : March 14, 2019
Last Update Posted : March 14, 2019
Sponsor:
Information provided by (Responsible Party):
Medicines Development for Global Health

Tracking Information
First Submitted Date  ICMJE August 23, 2016
First Posted Date  ICMJE January 6, 2017
Results First Submitted Date  ICMJE December 17, 2017
Results First Posted Date  ICMJE March 14, 2019
Last Update Posted Date March 14, 2019
Study Start Date  ICMJE January 2017
Actual Primary Completion Date March 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 12, 2019)
Mean Change From Baseline in QTc Interval (Corrected by Friderica's Formula, dQTcF) Associated With Plasma Moxidectin Concentrations After a Single Dose [ Time Frame: Baseline (pre-dose) and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 60, and 72 hours post dosing ]
Triplicate 10-second ECG recordings taken 1 minute apart using a Mortara continuous 12-lead digital ECG recorder connected to each subject during the Baseline to 72-hour post dose confinement period. Baseline only and baseline and placebo adjusted changes in QTc interval (corrected using the Friderica formula, QTcF) at each timepoint for each dose level were determined. The mean change from baseline (without and with placebo correction, dQTcF and ddQTcF respectively) at each of the 14 time points was calculated for each dose level. The primary outcome measure was the mean dQTcF for all subjects(the dQTcF gradient). The mean dQTcF for each active treatment group was determined at each post dose timepoint but the mean dQTcF by dose level was not calculated. The mean dQTcF at approximate moxidectin Tmax (hour 3 or hour 4) for each active treatment group and at hour 3 for the placebo group is reported.
Original Primary Outcome Measures  ICMJE
 (submitted: January 4, 2017)
ECG intervals in subjects receiving a single dose of moxidectin [ Time Frame: 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 60, and 72 hours post dosing ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 12, 2019)
Concentrations of Moxidectin in Plasma [ Time Frame: Pre-dose and at 0.5, 1, 2, 3, 4, 5, 6, 8, 12*, 24, 36, 48, 60, and 72 hours and days 8,15 and 22 post dosing ]
Concentrations of moxidectin in plasma were assessed by collection of plasma samples at pre-specified intervals after oral dosing with moxidectin. The concentration of moxidectin was determined using a validated LC MS/MS method.The pharmacokinetic time points coincided with ECG collection timepoints (within 5 minutes and no later than 10 minutes after ECG recordings). Plasma PK parameters were estimated from the concentration measurements, including maximum concentration (Cmax) for each individual and mean for each dose cohort.
Original Secondary Outcome Measures  ICMJE
 (submitted: January 4, 2017)
  • Concentration of moxidectin in plasma [ Time Frame: Pre-dose and at 0.5, 1, 2, 3, 4, 5, 6, 8, 12*, 24, 36, 48, 60, and 72 hours post dosing, and on Days 8, 15, and 22. ]
    Plasma PK
  • Concentration of moxidectin in urine [ Time Frame: Pre-dose and 0 to 24, 24 to 48, and 48 to 72 hours post dose ]
  • Concentration of moxidectin in faeces [ Time Frame: Pre-dose and 0 to 24, 24 to 48, and 48 to 72 hours post dose ]
  • Safety as assessed by occurrence of adverse events (AE) [ Time Frame: From baseline to end of study (At 12 weeks) ]
    All AE occurring during the study will be recorded
  • Safety as assessed by changes in laboratory results [ Time Frame: At Baseline and Days 2, 3, 4, 22 and Week 12 ]
    Hematology, serum chemistry, and urinalysis
  • Safety as assessed by changes in physical examination [ Time Frame: At Baseline and Days 1, 2, 3, 4, 8, 15, 22 and Week 12 ]
    Changes in physical examination findings including vital signs (heart rate, blood pressure, respiratory rate, temperature)
  • Safety as assessed by changes in 12-lead electrocardiograms (ECGs). [ Time Frame: At Baseline and Days 1, 2, 3, 4, 22 and Week 12 ]
    Changes in ECG intervals
Current Other Pre-specified Outcome Measures
 (submitted: March 12, 2019)
  • Subjects With Categorical Changes From Baseline in 12-lead Electrocardiograms (ECGs) [ Time Frame: At Baseline and Days 1, 2, 3, 4, 22 and Week 12 ]
    Changes from baseline in QTcF exceeding regulatory standard categorical limits (> 30msec change or exceeding 450msec). Report applies to changes of 30msec - </= 60msec only
  • Change From Baseline in Heart Rate (HR) and Duration of Other Interval Parameters (PR and QRS) [ Time Frame: Baseline (pre-dose) and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 60, and 72 hours post dosing ]
    Changes from Baseline were assessed at each timepoint up to 72 hours post dose. Mean changes across the 72 hour assessment period for each parameter were calculated for each moxidectin group and the placebo group and for the population overall.
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Effect of a Single Oral Dose of Moxidectin on the Cardiac QT Interval of Healthy Volunteers
Official Title  ICMJE A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Potential Effect of a Single Oral Dose of Moxidectin on the Cardiac QT Interval of Healthy Volunteers
Brief Summary

This study will investigate the effect of a single oral dose of moxidectin on the QT interval associated with moxidectin plasma concentrations.

The effect of moxidectin on other ECG intervals, and on safety, will also be assessed, as will preliminary pharmacokinetics and metabolism

Detailed Description

Moxidectin is being developed as a treatment for Onchocerciasis (river blindness), a serious, debilitating, disease caused by a parasitic worm, Onchocerca volvulus.

Five dose levels of moxidectin will be administered to healthy volunteers and ECG assessments undertaken at pre-specified pharmacokinetic time points to correlate QT interval with moxidectin concentration in plasma.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE QT Effects in Healthy Volunteers
Intervention  ICMJE
  • Drug: Moxidectin
    Moxidectin is a broad spectrum macrocyclic lactone endectocide
  • Other: Placebo
Study Arms  ICMJE
  • Experimental: Moxidectin 4mg
    10 subjects will receive a single oral dose of moxidectin 4mg
    Intervention: Drug: Moxidectin
  • Experimental: Moxidectin 8mg
    10 subjects will receive a single oral dose of moxidectin 8mg
    Intervention: Drug: Moxidectin
  • Experimental: Moxidectin 16mg
    10 subjects will receive a single oral dose of moxidectin 16mg
    Intervention: Drug: Moxidectin
  • Experimental: Moxidectin 24mg
    10 subjects will receive a single oral dose of moxidectin 24mg
    Intervention: Drug: Moxidectin
  • Experimental: Moxidectin 36mg
    10 subjects will receive a single oral dose of moxidectin 36mg
    Intervention: Drug: Moxidectin
  • Placebo Comparator: Placebo
    10 subjects will receive a single oral dose of placebo
    Intervention: Other: Placebo
Publications * Kinrade SA, Mason JW, Sanabria CR, Rayner CR, Bullock JM, Stanworth SH, Sullivan MT. Evaluation of the Cardiac Safety of Long-Acting Endectocide Moxidectin in a Randomized Concentration-QT Study. Clin Transl Sci. 2018 Nov;11(6):582-589. doi: 10.1111/cts.12583. Epub 2018 Sep 19.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: January 4, 2017)
60
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE May 2017
Actual Primary Completion Date March 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Healthy male between 18 and 50 years of age (inclusive);
  2. Body mass index (BMI) of 18 to 30 kg/m2 (inclusive) and a minimum weight of 50 kg (110 lbs);
  3. Biologically or surgically sterile or must commit to using a reliable method of birth control, in the opinion of the investigator, from Screening through the duration of the study;
  4. Willing and able to give written informed consent.

Exclusion Criteria:

  1. Unwilling to abstain from alcohol, caffeine, xanthine containing products, Seville oranges, grapefruit juices, and fish liver oils within 72 hours before Check in (Day -1) and throughout the inpatient period of the study;
  2. Less than 1 bowel movement every 24 hours in the absence of any laxative, suppository, or enema use during the month before Screening;
  3. Abnormal fecal consistency within 24 hours of Check in (Day -1);
  4. Clinically relevant abnormal findings on medical history, clinical laboratory test results, vital sign measurements, safety 12 lead ECG results, or physical examination at Screening or Baseline which, in the opinion of the investigator, would interfere with dosing, jeopardize the safety of the subject, or impact the validity of the study results;
  5. History of clinically significant dermatologic, gastrointestinal, renal, hepatic, neurologic, hematologic, endocrine, oncologic, pulmonary, immunologic, psychiatric, or cardiovascular disease or any other condition which, in the opinion of the investigator, would interfere with dosing, jeopardizes the safety of the subject, or impacts the validity of the study results;
  6. History or hypersensitivity or allergic reactions to ivermectin, moxidectin, or any of the ingredients in the study drug as described in the Investigator's Brochure;
  7. Any condition that may affect oral drug absorption (eg, previous surgery on the gastrointestinal tract including removal of parts of the stomach, bowel, liver, gall bladder, or pancreas);
  8. History of risk factors for torsades de pointes, including unexplained syncope, known long QT syndrome, heart failure, myocardial infarction, angina, or clinically significant abnormal laboratory assessments including hypokalemia, hypercalcemia, or hypomagnesemia. Subjects are also excluded if there is a family history of long QT syndrome or Brugada syndrome;
  9. A sustained supine systolic blood pressure >150 mm Hg or <90 mm Hg or a supine diastolic blood pressure >95 mm Hg or <50 mm Hg at Screening or Check in (Day -1). Blood pressure may be retested twice in the supine position. The blood pressure abnormality is considered sustained if either the systolic or the diastolic blood pressure values are outside of the stated limits after 3 assessments, and the subject will not to be randomized;
  10. A resting heart rate (HR) of <40 beats per minute (bpm) or >100 bpm when vital signs are measured at Screening or Check in (Day -1);
  11. An uninterpretable or abnormal screening ECG indicating a second or third degree atrioventricular block, or 1 or more of the following: QRS interval >110 milliseconds (msec); QT interval corrected by Fridericia's formula (QTcF) >450 msec; PR interval >200 msec; or any rhythm other than sinus rhythm that is interpreted by the investigator to be clinically significant;
  12. Concomitant use of prescription medications, including medications known to prolong the corrected QT interval (QTc) or herbal preparations, within 14 days or 5 half-lives (whichever is longer) before study drug dosing, or use of an over the counter (OTC) medication or vitamins within 7 days before study drug dosing;
  13. Received an investigational drug during the 30 days, or 5 half lives of the study drug (whichever is longer), before Check in (Day -1) or is planning to receive another investigational drug at any time during the study;
  14. History or presence of alcohol abuse (defined as consumption of more than 210 mL of alcohol per week, or the equivalent of fourteen 4 ounce [oz] glasses of wine or fourteen 12 oz cans/bottles of beer or wine coolers per week) within 6 months before Screening or positive alcohol test at Screening or Check-in (Day -1);
  15. History or presence of substance abuse within the past 2 years or positive drug screen test at Screening or Check in (Day -1);
  16. Current use or has used tobacco- or nicotine-containing products (eg, cigarettes, cigars, chewing tobacco, snuff, etc.) within 14 days before study drug dosing;
  17. Blood donation or significant blood loss within 30 days before Check-in (Day -1) or donated plasma within 7 days before Check-in (Day -1);
  18. Presence of hepatitis B surface antigen or antibodies to human immunodeficiency virus (HIV) or hepatitis C virus at Screening;
  19. Poor venous access in both arms;
  20. Unable to understand verbal or written English or any other language for which a certified translation of the informed consent form is available;
  21. For any reason, is deemed by the investigator or medically qualified designee to be inappropriate for this study, including a subject who is unable to communicate or cooperate with the investigator, and/or is unwilling to comply with protocol defined procedures and complete the study.
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Ages  ICMJE 18 Years to 50 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03012828
Other Study ID Numbers  ICMJE MDGH-MOX-1008
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Plan Description: Healthy volunteer study: results are not useful to individuals
Responsible Party Medicines Development for Global Health
Study Sponsor  ICMJE Medicines Development for Global Health
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Mark Sullivan Sponsor GmbH
PRS Account Medicines Development for Global Health
Verification Date March 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP